Epigenetic modifications modulate chromatin states to regulate gene expression. Among them, DNA methylation and histone modifications play a crucial role in the establishment of the epigenome. In cancer, these epigenetic events may act in concert to repress tumor suppressor genes or promote oncogenic pathways. In the context of cancer initiation and progression, recruitment of DNA (cytosine-5)-methyltransferases to specific genomic regions is mainly mediated by histone epigenetic marks, transcription factors and co-regulators as part of a dynamic process. Herein, we will review these mechanisms and present state-of-the-art of DNA methylation, treatment and development of epigenetic cancer therapies targeting this epigenetic modification.